Percutaneous transluminal coronary angioplasty (PTCA) has become a routine mode of therapy to relive arterial luminal stenosis in patients with coronary artery disease. Other trans-catheter interventional techniques, such as laser devices, mechanical atherectomy, and endovascular stents are currently being used in human patients. The "Achilles heel" of all interventional intravascular techniques is the phenomenon of arterial restenosis that occurs within 3 months after the PTCA in about 30% of the patients. It is likely that damage to the vessel wall during the arterial stretch at the time of angioplasty causes smooth muscle cell proliferation and the subsequent development of restenosis. Thus, restenosis is a healing phenomenon resulting from arterial injury and is independent of the atherosclerotic process. Efforts to gain better understanding of this phenomenon have been confounded by the lack of an appropriate animal restenosis model. By applying localized mechanical pressure to a rabbit artery, disruption of the normal histological architecture of the arterial wall occurs. As a result, striking smooth muscle cell proliferation occurs in the media of the vessel; a histopathologic reaction similar to human restenosis. In a preliminary study, this phenomenon was highly reproducible (75%). We are now beginning a series of experiments in which we plan to selectively inhibit the process of smooth muscle proliferation with a variety of genetically engineered peptides and toxins. Endpoints of the studies will relate to the degree of smooth muscle cell proliferation and extent of narrowing of the vessel lumen.